Articular cartilage plays an essential role in the movement of mammalian joints. While synovial fluid within the joint cavity serves as a lubricant, the articular cartilage provides a superior smooth surface between adjacent bones, allowing for near-frictionless motion of joints. It is the articular cartilage that spreads compressive stresses over the articular plate surfaces of the joint, thus protecting weight-bearing bones from shattering.
Articular cartilage is composed of chondrocytes embedded in an extracellular matrix of proteoglycans, collagen, and small molecular weight glycoproteins. Proteoglycans are essential in maintaining strength of the cartilage tissue so that it can withstand compression. Collagen provides the tissue with tensile strength and resistance to shear. In a healthy joint, the extracellular matrix is maintained by a balance between the synthesis and secretion of these macromolecules by chondrocytes and their subsequent degradation by proteolytic enzymes such as proteoglycanases and metalloproteinases, which are also synthesized and secreted by chondrocytes. Damage to the articular surface can disrupt this equilibrium, such that degradation exceeds the ability of chondrocytes to synthesize macromolecules necessary for repair of the cartilage tissues. This disequilibrium results in loss of extracellular matrix or alteration of the material properties of the cartilage tissue. Moreover, with trauma-related injuries, chondrocytes do not regenerate and are incapable of repairing focal defects or cartilage tears. The range of motion for a joint sustaining such an injury can be severely affected.
Chronic disruption of the equilibrium between synthesis and degradation of cartilage matrix macromolecules is associated with the development of osteoarthritis, the most common of the arthritic disorders in humans. As osteoarthritis progresses, the cushioning surface of the affected joint thins as the cartilage softens. Vertical clefts develop, and the integrity of the surface is breached. Cartilage ulcers, appositional bone growth, and osteophytes may appear and restrict movement. When left untreated, continued excessive degradation of proteoglycans and collagens by proteases ultimately leads to total loss of cartilage and eburnation of bone.
Historically, treatment of osteoarthritis and articular cartilage injuries has been limited to pain relief, reduction of joint loading, physical therapy, and orthopedic surgery, all of which are aimed at symptomatic relief rather than treatment of the underlying pathologic disorder. More recently, osteoarthritis research has concentrated on development of “chondroprotective” methods. Such methods involve long-term therapeutic treatment aimed at preserving or stimulating cartilage formation (see Rogachefsky et al. (1993) Osteoarthritis and Cartilage 1:105–114; Issebelcher et al. (eds.) Harrison's Principles of Internal Medicine (13th ed.; McGraw-Hill Inc., 1994), pp. 1692–1697).
A number of studies have focused on the physiological role of insulin-like growth factor I (IGF-I) on chondrocytes and the generation of extracellular matrix of normal articular cartilage. IGF-I has been shown to stimulate in vitro chondrocyte cell proliferation (see, for example, Osborne et al. (1989) J. Orthop. Res. 7: 35–42; and Trippel et al. (1989) Pediatr. Res. 25: 76–82), and it stimulates proteoglycan and collagen synthesis by chondrocytes of normal articular cartilage in both in vitro and ex vivo explant studies (see, for example, Guenther et al. (1982) Experientia 38: 979–981; Willis and Liberti (1985) Biochim. Biophys. Acta 844: 72–80; McQuillan et al. (1986) Biochem. J. 240: 423–430; and Tesch et al. (1992) J. Orthop. Res. 10: 14–22). These stimulatory actions are mediated through the IGF-I receptor in chondrocyte cells (see Taylor et al. (1988) FEBS Lett. 236: 33–38).
Recent studies have examined the physiological function of IGF-I in the etiopathogenesis of osteoarthritis. Expression level of IGF-I apparently increases with the advancement of osteoarthritis pathology (see Middleton and Tyler (1992) Ann. Rheum. Dis. 51: 40–447); Middleton et al. (1996) J. Histochem. Cytochem. 44: 133–141; and Keyszer et al. (1995) J. Rheumatology 22: 275–281). However, articular cartilage responsiveness to IGF-I has been shown to decrease in an experimental arthritis model (see Joosten et al. (1989) Agents Actions 26: 193–195). This lack of responsiveness may be associated with decreased synthesis of the IGF-I receptor (see Joosten et al. (1989), increased degradation of IGF-I and/or its receptor (Schalkwijk et al. (1989) Arthritis Rheum. 82: 66–71) by extracellular proteolytic enzymes, or by the presence of IGF-I binding proteins at the chondrocyte cell surface or by nonspecific binding of IGF-I to the cartilage matrix thereby blocking access of IGF-I to its receptor sites and negating any potential benefit of increased synthesis of IGF-I and/or its receptor (Dore et al. (1994) Arthritis and Rheumatism 37: 253–263).
Parenteral administration of IGF-I has been referred to as a method for enhancing muscle mass of atrophied skeletal muscle in a joint having reduced function due to disease, such as osteoarthritis, or trauma-related injuries (see U.S. Pat. No. 5,444,047).
Recently, IGF-I has been evaluated in vivo for its therapeutic effect in the treatment of osteoarthritis (Rogachefsky et al. (1993) Osteoarthritis and Cartilage 1: 105–114). In this study, dogs subjected to anterior cruciate ligament transection were subsequently examined for symptoms of osteoarthritis. Three weeks after transection, 1.0 μg of human recombinant IGF-I was administered intra-articularly 3 times per week for 3 weeks. Results of this study showed that intra-articular administration of IGF-I alone was ineffective in treating osteoarthritis, as cartilage in treated animals was not different from cartilage in untreated animals.
Clearly better methods for treating cartilage disorders or injuries are needed.